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Bone Marrow Transplantation (2004) 34, 477–483 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00 www.nature.com/bmt Conditioning regimens High-dose treosulfan in patients with relapsed or refractory high-grade lymphoma receiving tandem autologous blood stem cell transplantation M Koenigsmann1, M Mohren1, K Jentsch-Ullrich1, A Franke1, E Becker2, M Heim2, M Freund3 and J Casper3 1Clinic of Hematology/Oncology, Germany; 2Institute for Transfusion Medicine and Immunohematology, Germany; and 3University Magdeburg and Clinic of Hematology/Oncology, University Rostock, Germany Summary: cytostatic agents include cyclophosphamide, etoposide, melphalan, BCNU, cytarabine and platinum compounds. This phase I/II study evaluated high-dose treosulfan in The alkylating drug busulfan has been used for 30 years in patients with high-grade lymphoma. In all, 21 patients high-dose therapy. It is characterized by profound stem cell (median age 51, 25–60 years) with primary refractory toxicity and cytotoxic activity in various hematological disease (n ¼ 3) or early (n ¼ 11) or late (n ¼ 7) relapse malignancies.3 Major drawbacks associated with busulfan received DexaBEAM and one course etoposide for include the high incidence of veno-occlusive disease cytoreduction and PBPC mobilization. Subsequently, 16 (VOD),4,5 a high variance of bioavailability, drug interac- patients received 30 g/m2 treosulfan and 140 mg/m2 tions associated with enzymatic activation in the liver6,7 and melphalan, followed by autologous transplantation. Nine finally a decreased threshold of seizure activity.8 patients received a 2nd high-dose treatment (HDT) with Treosulfan is a prodrug of a bifunctional alkylating 30 g/m2 treosulfan and 750 mg/m2 thiotepa. Recovery time cytotoxic agent with close structural similarity to busulfan,9 to 41/nl leukocytes and 425/nl thrombocytes was 8.9 which has been used for the treatment of ovarian cancer for (range 8–11) and 11.9 (8–16) days after 1st and 9.6 (7–13) many years.10,11 Myeloablative dose escalation upto 56 g/ and 13 (9–19) days after 2nd HDT. Reversible grade 3 or 4 m2 has recently been tested, and the maximum-tolerated nonhematologic toxicities included mucositis (n ¼ 7), dose (MTD) is 47 g/m2.12 Treosulfan can be given infection (n ¼ 7) and one episode of re-entry tachycardia. intravenously (i.v.) and is activated nonenzymatically, Two treatment-related deaths occurred after 2nd HDT. yielding highly reproducible pharmacokinetic profiles.13 Since three dose-limiting toxicities occurred among nine Owing to its antineoplastic activity and limited organ patients receiving tandem HDT, 30 g/m2 of treosulfan was toxicity, high-dose treosulfan has been considered for considered MTD in this setting. Patients with late autologous peripheral blood stem cell transplantation. compared to early relapse or refractory disease had a Recent in vitro data show activity in myeloma cells.14 higher probability of CR (6/7 vs 3/14 patients, P ¼ 0.017) Profound stem cell toxicity has been demonstrated in a and overall survival (71 vs 21%, Po0.05, 24–49 months preclinical model and it has been hypothesized that follow-up). In conclusion, high-dose treosulfan as major treosulfan, similar to busulfan, may also kill immature therapy component induces sustained complete remissions malignant progenitor cells.15 Most recently, treosulfan has in relapsed high-grade lymphoma with acceptable toxicity. been combined with fludarabine as a conditioning treat- Bone Marrow Transplantation (2004) 34, 477–483. ment in allogeneic stem cell transplantation.16 In the doi:10.1038/sj.bmt.1704626 following phase I/II trial for patients with relapsed and Published online 2 August 2004 refractory high-grade lymphoma, we tested the feasibility, Keywords: treosulfan; relapsed high-grade lymphoma; the MTD, and the efficacy of high-dose treosulfan in a autologous PBPC transplantation; tandem transplantation tandem high-dose approach. High-dose chemotherapy with autologous stem cell trans- Materials and methods plantation can achieve long-term remission in patients with 1,2 relapsed high-grade lymphoma. Frequently employed Patient selection The study was open to adults up to 60 years of age with relapsed or refractory high-grade lymphoma who had Correspondence: Dr M Koenigsmann, Klinik fu¨ rHa¨ matologie und received chemotherapy with or without radiotherapy for Onkologie, Otto-von-Guericke-Universita¨ t, Leipziger Strasse 44, their primary lymphoma manifestation. Patients were Magdeburg 39120, Germany; E-mail: [email protected] considered refractory to the primary treatment if they Received 9 February 2004; accepted 9 May 2004 never achieved at least PR. Early or late relapse was defined Published online 2 August 2004 as relapse within or beyond 1 year after primary diagnosis.2 High-dose treosulfan in relapsed high-grade lymphoma M Koenigsmann et al 478 Patients with antecedent or concurrent neoplastic disease stem cell transplantation followed on day 0, and filgrastim were excluded. The protocol was started in October 1999 was given as described above. after approval by the local ethical committee. Patients were treated after giving written informed consent. Study design and toxicity evaluation Induction therapy and stem cell mobilization One principle goal of the study was to evaluate dose- limiting toxicities (DLT) and to determine the MTD of For cytoreduction and stem cell mobilization (back-up), all high-dose treosulfan in combination with either melphalan patients were scheduled to receive one cycle of DexaBEAM or thiotepa. During hospitalization, clinical and laboratory with dexamethasone 3 Â 8 mg on treatment days 1–10, side effects were monitored daily and analyzed according to BCNU 60 mg/m2 on day 2, melphalan 20 mg/m2 on day 3, the CTC criteria of the National Cancer Institute (version etoposide 75 mg/m2 and cytarabine 100 mg/m2 every 12 h, 3.0). DLT was defined as any of the following toxicities: each on days 4–7. Filgrastim at 10 mg/kg/day was started on nephrotoxicity Xgrade 2, neurotoxicity Xgrade 2, other day 11 and was continued until the end of stem cell nonhematological toxicity Xgrade 3 (excluding alopecia, collection. Subsequently, another induction course was to nausea/vomiting, infections, mucositis grade 4 shorter than be given with etoposide at 2 g/m2 followed again by 7 days, and diarrhea grade III). The MTD was defined as filgrastim at 10 mg/kg/day for stem cell collection. Owing one dose level below the level at which greater than or equal to the additional in vivo purging effect, the second graft was to two of three or three of six patients experienced DLT, preferentially to be used for transplantation. At least respectively. 4 Â 106 CD34 þ cells/kg body weight (b.w.) had to be collected to provide for two stem cell transplantations. Response evaluation Stem cell collection The other principle goal of the study was to evaluate the efficacy of the treatment at the MTD. Complete restaging As soon as the CD34 þ cell count exceeded 10/ml, PBPCs was performed including clinical and laboratory workup as were collected using a blood cell separator (Spectra, COBE well as a CT scan after the completion of the two sequential BCT Inc., Lakewood, CO, USA) with a semiautomated induction courses, immediately before the 2nd high-dose mononuclear cell collection program. The separation was cycle and 2 months after the last HDT. Complete remission continued until the necessary amount of CD34 þ cells was was defined as disappearance of all lymphoma manifesta- collected or until the number of circulating CD34 þ cells tions for at least 8 weeks. Partial response was defined as a fell below the 10/ml threshold. If possible, peripheral veins more than 50% reduction of all evaluable tumor lesions for were used; otherwise, a central venous catheter was placed a duration of at least 8 weeks. Time to progression and in the internal jugular vein. Blood flow was between 50 and survival time were calculated from the date of entry into the 90 ml/min, and the separation volume was the 2.5-fold of study protocol. the blood volume. The ration of whole blood to antic- Follow-up visits were scheduled for every 3 months oagulation ratio was kept regulated at 18:1, using mixed during the first year, every 4 months during the second anticoagulation with 3000 IU heparin to 600 ml ACDA year, and every 6 months thereafter. In addition to clinical (Fresenius, Hemocare). Cells were mixed with DMSO at a and laboratory testing, CT scans were performed twice a final concentration of 10% in freezing bags (Consarctic), year in the first 2 years and once a year thereafter. subjected to controlled-rate freezing (BV-25, Consarctic) and stored in liquid nitrogen under controlled standard conditions. Statistics The influence of relapse situation (refractory and early High-dose treatment relapse vs late relapse) on the achievement of complete remission was tested with Fisher’s exact test. Survival The first high-dose therapy consisted of melphalan 140 mg/ curves were calculated according to the Kaplan–Meier 2 m , given on day À4 as an i.v. infusion over 30 min, and method. Comparison of survival curves was made by the 2 treosulfan 30 g/m , given on day À3 as an i.v. infusion over log-rank test. 24 h. After the transplantation of at least 2 Â 106 CD34 þ cells/kg b.w. on day 0, filgrastim was given s.c. at 5 mg/kg/ day from day 1 until neutrophil recovery 41.5/nl. The þ Results second high-dose therapy course was to be given 8–12 weeks after the first one. It contained treosulfan and Patient characteristics (Table 1) thiotepa. Treosulfan was split into daily doses of 10 g/m2, and was given on days À5, À4, and À3, each time as an i.v.

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